Expert Critique

It has long been established that patients with cancer have an increased risk of developing a second cancer. This increased risk is multifactorial and related to genetic factors, environmental factors, and/or treatments for the initial cancer. In multiple myeloma (MM), the risk of second cancers has only recently gained greater attention as novel therapies have improved overall survival. The article by Chen et al adds to the growing data emerging regarding second malignancies in MM.

That paper examines the rates of second malignancies in MM patients in Germany and Sweden and compares these with the expected rate of first cancers in the population. The strengths of the study include the large sample of patients included and the high quality of the database for extraction. As noted, the study showed that the rankings of cancers were generally similar across the two populations. The authors suggest that this similarity might point to an underlying mechanism contributing to these second cancers. It should be remembered, however, that the incidence rates of these other cancers were generally not different for patients with MM versus the general population (in 2012). Therefore, while this similarity in ranking might indeed suggest a common mechanism, this mechanism is not likely related to the MM diagnosis, and is more likely related to more global epidemiologic similarities in the 2 populations.

The researchers also noted an increased risk of AML across the 2 study populations, finding that the risk of increased acute myelogenous leukemia (AML) differed by the time of diagnosis, with patients diagnosed before 2006 having an increased risk compared with patients diagnosed between 2006 and 2010.

The researchers suggest that this may be due to a difference in therapy, with reduced usage of alkylators after the advent of novel therapies. However, no data on therapy is available upon which to base this assumption, and indeed, melphalan is still used as a conditioning agent prior to transplant.

The researchers also found that the risk of AML in Germany was highest for patients with more than 5 years of follow-up, and was also elevated after 5 years in Sweden, though not reaching statistical significance. Follow-up data on second malignancies was capped at 2010, so it is possible that the cohort of patients diagnosed after 2006 lacked sufficient follow-up to fully capture the risk of second cancers, including AML.

Therefore, while the data from Chen and others (Morton) make a compelling case for an increased risk of second cancers after a diagnosis of MM, particularly a higher risk for AML, it is premature to suggest that the risk is declining with modern therapy. Indeed, data suggest that the rates of second cancers are increased in the modern age with the use of immunomodulators when used after alkylators. Therefore, continued vigilance and study is required to fully appreciate the risk and etiology of second malignancies in MM.

Full Critique

Patients with multiple myeloma are living longer than ever before, thanks to major advances in treatment. However, an unintended and unwelcome consequence of longer survival for these patients, investigators say, is a steady rise in the incidence of second primary cancers.

Since the 1960s, oncologists have been aware that alkylating agents such as melphalan, commonly used in high-dose regimens for treatment and pre-transplant conditioning of patients with multiple myeloma, are associated with increased risk for treatment-related leukemia.

Now, drawing on comprehensive European cancer registries, investigators in Sweden, Germany, and the United States have found that patients with multiple myeloma have an approximately two- to five-fold higher risk for developing acute myeloid leukemia (AML), as well as elevated risks for kidney cancer and nervous system cancers compared with the general population.

"Although their exact underlying biologic mechanisms have not been well characterized, treatment-related factors may contribute in addition to inherited genetic predisposition and shared non-genetic factors," wrote Tianhui Chen, MD, PhD, from the German Cancer Research Centre in Heidelberg, Germany, in Scientific Reports.

The investigators, which included the GEKID Cancer Survival Working Group, looked at data on patients age 15 and older at the time of a multiple myeloma diagnosis. Chen et al identified survivors enrolled in Sweden's nationwide cancer registry and 12 German cancer registries. For each cohort, standardized incidence ratios (SIRs) were calculated to estimate the relative risks that patients would develop specific second primary malignancies compared with the general population in their region.

In all, 752 of the 18,735 myeloma survivors in the German registries developed a second primary cancer, as did 349 of 7,560 survivors in the Swedish registry. In each country, prostate cancer was the most common second primary cancer, followed by colorectal cancer. Except for a higher frequency of stomach cancer in Germany than in Sweden, and more frequent nervous system cancers in Sweden than in Germany, the rankings of various cancers were generally similar, the authors found.

When they looked at the risks for specific malignancies both in the overall population and by period of diagnosis, they found that in Germany, the only significantly elevated SIR in the overall population was for leukemia (SIR 1.7, 95% CI, 1.2-2.4).

The investigators noted that the increased SIRs for leukemia were accounted for by AML: In Germany, the SIR for AML was 4.9, 95% CI, 3.2-7.3, and the SIR in Sweden was 2.3, 95% CI, 1.2-4.0).

The researchers also found that the elevated risk for AML was greater for earlier periods of diagnosis, suggesting a possible effect of changes in treatment practice. For example, in Germany the SIR for AML for patients diagnosed with multiple myeloma from 1997 through 2003 was 9.7 (95% CI, 4.2-19), compared with 3.5 (95% CI, 1.5-6.9) for those diagnosed from 2004 through 2010. The respective SIRs in Sweden by time period were 3.8 (95% CI, 1.4-8.3) compared with 2.2 (95% CI, 0.3-7.8).

Alkylators Suspected

Patient exposure to alkylating agents such melphalan and cyclophosphamide, either with or without immunomodulators such as thalidomide, were likely to have been more common in the earlier diagnosis periods, prior to the advent of proteasome inhibitors and other therapies, which could explain the higher risk for AML, the investigators speculated.

"Therefore, these patients might have been exposed to high doses of alkylating agents in the earlier years of diagnosis. However, after the dawn of the new millennium, alkylating agents might not have been used as intensively and frequently as in earlier diagnosis periods because of the introduction of the novel agents. In the later periods, survival from multiple myeloma diagnosis improved markedly, and long-term survivors from both diagnosis periods accumulated. Therefore, AML as a long-term side effect from alkylating agents, as described from other cancer entities such as testicular and ovarian cancers, was more likely to evolve on long-term follow-up."

Looking at the issue from another angle, Lindsay M. Morton PhD, from the Division of Cancer Epidemiology and Genetics at the National Cancer Institute in Bethesda, Md., and colleagues reported at the 2015 annual meeting of the American Society of Hematology that among 746,007 adults with various cancers who were initially treated with chemotherapy from 2000 through 2012 and survived for at least 1 year after diagnosis, the SIR for treatment-related AML or myelodysplastic syndromes (MDS) was 4.1 (95% CI, 3.9-4.2), and that the risk for treatment-related AML/MDS for patients diagnosed with multiple myeloma was six-fold compared with general population (SIR 6.3, 95% CI. 5.1-7.6).

Chen and co-authors and Morton and co-authors reported having no conflicts of interest.

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